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Institut de Biologie StructuraleGrenoble / France

Contact person(s) related to this article / LORTAT-JACOB Hugues

Presentation of the Structure and Activity of Glycosaminoglycans Group

Group leader : Hugues Lortat-Jacob

Members

Permanent members :

  • Hugues Lortat-Jacob (DR1 CNRS)
  • Rabia Sadir (Engineer CEA)
  • Romain Vivès (DR2 CNRS)
  • Damien Maurin (Engineer assistant CNRS)

Contractual members :

  • Yoan Monneau (Post-doc; April 2014 - March 2016)
  • Lynda Djerbal (PhD student ; September 2015 - September 2018)
  • Rana El Masri (PhD student ; February 2016- February 2019)

Research topics

Our researches focus on a group of polysaccharides collectively known as glycosaminoglycans (GAGs) which comprise heparin, heparan sulphate, chondroitin and dermatan sulphate, keratan sulphate and hyaluronic acid.

GAGs are widely distributed in vivo. They are present in large amounts in every tissue both at the cell surface, where they importantly contribute to the glycocalix, and within the extracellular matrix. They exert their biological functions by interacting with a large array of proteins (cytokines, growth factors …) thereby modifying their structure and reactivity. Present at the cell - extracellular milieu interface, GAGs are strategically located to regulate most of the processes that occur at the cell membrane level (cell-cell communication, signalling, cell-matrix interactions, interactions with pathogens …).

In that context, our work aims in particular at:

  • Identifying the structural determinants involved in GAG-protein binding reactions.
  • Understanding the cellular mechanisms regulating the saccharide structure of GAGs.
  • Describing the mechanisms by which GAGs control protein activities.

The experimental models used are (1) pathogen attachment and entry into host cells and (2) the immune system. The characterisation of complexes between viral/bacterial proteins or cytokines and GAGs leads to the engineering of anti-infectious or anti-inflammatory oligosaccharides.
In addition, a number of methodological approaches (including GAG-on-chip; sequencing; NMR) are developed for the analysis of GAG/protein interactions.

Key word: Glycosaminoglycan - heparan sulfate - Glycobiology - Receptor - Interaction - Cytokines - Immunity - Host-Pathogen interactions – Virology - Infectious diseases - Chemo-enzymatic approaches - Methods developments

Specific techniques

  • Production, purification, biochemical and structural characterisation of glycosaminoglycans
  • Production, purification and characterisation of recombinant proteins
  • Cellular biology
  • Kinetic analysis of interactions (BIAcore technology)
  • Peptide sequencing at the protein-glycosaminoglycan interface
  • NMR based structural approaches.

Available services

Disaccharide analysis of glycosaminoglycans

Major publications

  • Arien K.K., Baleux F., Desjardins D., Porrot F., Coic Y.-M., Michiels J., Bouchemal K., Bonnaffé D., Bruel T., Schwartz O., Le Grand R., Vanham G., Dereuddre-Bosquet N. and Lortat-Jacob H. CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge. Scientific Reports 6, 34829 (2016)
  • Connell B.J., Sadir R., Baleux F., Laguri C., Kleman J-P., Luo L., Arenzana-Seisdedos F. and Lortat-Jacob H. Heparan Sulfate differently regulates CXCL12α and CXCL12γ mediated chemotaxis through differential presentation to CXCR4. Science Signaling 9, ra107 (2016)
  • Pegeot P., Sadir R., Eriksson I., Kjellen L., Simorre J.P., Gans P., and lortat-Jacob H. Profiling sulfation/epimerization pattern of full-length heparan sulfate by NMR following cell culture 13C-glucose metabolic labelling. Glycobiology 25, 151-156 (2015)
  • Préchoux A., Halimi C., Simorre J.P., Lortat-Jacob H. and Laguri C. C5-epimerase and 2-O-sulfotransferase associate in vitro to generate contiguous epimerized and 2-O-sulfated heparan sulfate domains. ACS ChemBiol 10, 1064-1071 (2015)
  • Beckouche N., Bignon M., Lelarge V., Mathivet T., Pichol-Thievend C., Berndt S., Hardouin S, Garand M., Ardidie-Robouant C., Barret A., Melino G., Lortat-Jacob H., Muller L., Monnot C. and Germain S. The interaction of heparan sulfate proteoglycans with endothelial transglutaminase-2 limits VEGF165-induced angiogenesis. Science Signaling 8, ra70 (2015)
  • Migliorini E., Thakar D., Kühnle J., Sadir R., Dyer D.P., Li Y., Sun C., Volkman B.F., Handel T.M., Coche-Guerente L., Fernig D.G., Lortat-Jacob H. and Richter R.P. Cytokines and growth factors cross-link heparan sulfate. Open Biology 5, 150046 (2015)
  • Vivès R.R., Seffouh A. and Lortat-Jacob H. Post-synthetic regulation of Heparan Sulfate structure: the yin and yang of the Sulfs in Cancer. Front. Oncol. 3:331. doi: 10.3389/fonc.2013.00331 (2014)
  • Saesen E, Sarrazin S, Laguri C, Sadir R, Maurin D, Thomas A, Imberty A and Lortat-Jacob H. Insights into the mechanism by which Interferon-gamma basic amino acid clusters mediate protein binding to heparan sulfate. J. Am. Chem. Soc. 135, 9384−9390 (2013)
  • Seffouh A, Milz F, Przybylski C, Laguri C, Oosterhof A, Bourcier S, Sadir R, Dutkowski E, Daniel R, van Kuppevelt TH, Dierks T, Lortat-Jacob H, and Vivès RR. HSulf sulfatases catalyse processive and orientated 6-O-desulfation of heparan sulfate that differentially regulate fibroblast growth factor activity FASEB J. 27, 2431-2439
    (2013)
  • Connell BJ, Baleux F, Coic YM, Clayette P, Bonnaffé D and Lortat-Jacob H. A synthetic heparan sulfate-mimetic peptide conjugated to a mini CD4 displays very high anti-HIV-1 activity independently of coreceptor usage. Chemistry & Biology 19, 131-139 (2012)
  • Laguri C, Sapay N, Simorre J-P, Brutscher B, Imberty A, Gans P and and Lortat-Jacob H. 13C-labeled heparan sulfate analogue as a tool to study protein/heparan sulfate interaction by NMR spectroscopy. Application to the CXCL12α chemokine. J. Am. Chem. Soc. 133, 9642-9645 (2011)
  • Baleux F, Loureiro-Morais L, Hersant Y, Clayette P, Arenzana-Seisdedos F, Bonnaffé B and Lortat-Jacob H. A synthetic CD4-HS glycoconjugate inhibits both CCR5 and CXCR4 HIV-1 attachment and entry. Nat. Chem. Biol. 5, 743-748 (2009)
  • Lortat-Jacob H. The molecular basis and functional implications of chemokine interactions with heparan sulphate. Curr. Opin. Struct. Biol. 19, 543-548 (2009)
  • Crublet E, Andrieu J-P, Vivès RR, and Lortat-Jacob H. The HIV-1 envelope glycoprotein gp120 features four heparan sulfate binding domains, including the coreceptor binding site. J. Biol. Chem. 283, 15193-15200 (2008)
  • Vivès RR, Imberty A, Sattentau QJ, and Lortat-Jacob H. Heparan sulphate targets the HIV-1 envelope glycoprotein gp120 coreceptor binding site. J. Biol. Chem. 279, 54327-54333 (2005)
  • Sarrazin S, Bonnaffé D, Lubineau A, and Lortat-Jacob H. Heparan sulfate mimicry: A synthetic glycoconjugate that recognizes the heparin-binding domain of IFNγ inhibits the cytokine activity. J. Biol. Chem. 280, 37558-37564 (2005)
  • Lortat-Jacob H, Grosdidier A, and Imberty A. Structural diversity of heparan sulphate binding domains in chemokines. Proc. Natl. Acad. Sci. USA 99, 1229-1234 (2002)
  • Sweeney EA, Lortat-Jacob H, Priestley GV, Nakamoto B, and Papayannopoulou T. Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Blood 99, 44-51 (2002)
  • Reeves EP, Lu H, Lortat-Jacob H, Messina CGM, Bolsover S, Gabella G, Potma EO, Warley A, Roes J, and Segal AW. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416, 291 - 297 (2002)
  • Vivès R, Crublet E, Andrieu JP, Gagnon J, Rousselle P, and Lortat-Jacob H. A novel strategy for defining critical amino acid residues involved in protein/GAG interactions. J. Biol. Chem. 279, 54327-54333 (2004)

A list of all publications since 2000 can be found here.

Thesis

A list of Ph.Ds. can be found here.